SEX DIFFERENCES AND ESTROGEN RECEPTORS REGULATE DENDRITIC CELLS IN INFLAMMATION Abstract Autoimmune diseases such as rheumatoid arthritis and multiple sclerosis are strongly female biased, yet the cellular and molecular basis for this is not understood. Immune cells and their progenitors in females and males express estrogen receptors (ER). However we still lack fundamental information about how ER signaling in response to physiological levels of estrogens regulates the development and function of specific immune cells in either sex, although such comparisons are expected to yield critical insights into sex-based differences in normal immunity and autoimmunity. An attractive hypothesis is that differences in sex hormone levels or signaling through their receptors shift thresholds of inflammatory immune responses and thus contribute to the strong sex biases in incidence of autoimmune disease. My laboratory and others have identified estradiol and ER1 signaling as critical regulators of differentiation and activation of dendritic cells (DC), antigen presenting cells essential for initiation of innate and adaptive immunity. We demonstrated that ER1 signaling in myeloid progenitors induces an elevated amount of the transcription factor interferon regulatory factor 4 (IRF4), which leads to a developmental program underlying CD11b+ DC differentiation. Using competitive ER1+/ER1-/- BM chimeras, we have shown that ER1 expression regulates DC development and activation in vivo. Based on these studies and other preliminary results, we propose that ER1 signaling regulates DC development and function during homeostasis and inflammation. In this project, we will evaluate three distinct mechanisms by which ER1 signaling might influence DC-mediated immune responses in vivo: (1) regulation of hematopoietic progenitor numbers and capacity for DC differentiation during homeostasis;(2) regulation of de novo DC development from inflammatory monocytes (iMO) or other DC precursors during adjuvant-induced inflammation and autoimmunity;(3) regulation of the functional responses of mature DC during adjuvant- induced inflammation and autoimmunity. We will address these questions using novel models including competitive ER1+/ER1-/- BM chimeric mice and mice in which ER1 deficiency is restricted to particular populations of DC, MO or M&. These new models will be particularly insightful because they will determine how ER1 signaling in response to physiological levels of endogenous estrogens regulates de novo DC development and functional responses during inflammation and autoimmunity in both sexes. This study will provide the fundamental knowledge required for development of novel therapies involving ER modulators to reduce the incidence or severity of immune system diseases. PUBLIC HEALTH RELEVANCE: Cells of the human and murine immune systems are capable of responding to natural estrogens, environmental estrogen-like compounds, and drugs used for treatment of breast cancer and osteoporosis. We seek to understand how estrogens control the development and function of key regulatory cells of the immune system, termed dendritic cells, during inflammation. This knowledge will help to understand why autoimmune diseases preferentially afflict women.